Persistent negative and cognitive symptoms are a primary cause of chronic disability and poor long-term outcome in schizophrenia. Phencylidine (PCP) and other antagonists of N-methyl-D-aspartate (NMDA)-mediated neurotransmission induce symptoms and cognitive deficits that closely resemble those of schizophrenia, indicating a potentially critical role of NMDA receptors in the etiopathology of primary negative symptoms, NMDA receptors are modulated in vivo by glycine and D-serine, which bind to a modulatory site of the NMDA receptor complex. Clinical trials with NMDA/glycine site agonists have yielded highly encouraging clinical data. The present project will focus on development of D-serine as an effective treatment for persistent negative symptoms and cognitive dysfunction in schizophrenia. An initial series of investigations will investigate dose response relationships of D-serine based upon a series of PK/PD studies. These studies will be used to determine best available clinical dose both for this Project and for parallel prodromal studies to be conducted under Project 2. A subsequent double-blind will seek to obtain phase II level data supporting clinical effectiveness of D-serine in schizophrenia. Together, these studies will validate use of D-serine as a clinically effective and feasible treatment for persistent negative symptoms of schizophrenia, and will permit and encourage continued pharma-based development of this compound.